Sampling variability of liver biopsy in nonalcoholic fatty liver disease

BACKGROUND & AIMS: In nonalcoholic fatty liver disease (NAFLD), the distinction between steatosis and steatohepatitis (NASH) and the assessment of the severity of the disease rely on liver histology alone. The aim of this study was to assess the sampling error of liver biopsy and its impact on the diagnosis and staging of NASH. METHODS: Fifty-one patients with NAFLD underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the kappa reliability test. RESULTS: No features displayed high agreement; substantial agreement was only seen for steatosis grade; moderate agreement for hepatocyte ballooning and perisinusoidal fibrosis; fair agreement for Mallory bodies; acidophilic bodies and lobular inflammation displayed only slight agreement. Overall, the discordance rate for the presence of hepatocyte ballooning was 18%, and ballooning would have been missed in 24% of patients had only 1 biopsy been performed. The negative predictive value of a single biopsy for the diagnosis of NASH was at best 0.74. Discordance of 1 stage or more was 41%. Six of 17 patients with bridging fibrosis (35%) on 1 sample had only mild or no fibrosis on the other and therefore could have been under staged with only 1 biopsy. Intraobserver variability was systematically lower than sampling variability and therefore could not account for most of the sampling error. CONCLUSIONS: Histologic lesions of NASH are unevenly distributed throughout the liver parenchyma; therefore, sampling error of liver biopsy can result in substantial misdiagnosis and staging inaccuracies.     

非酒精性脂肪性肝病患者肝组织抵抗素的表达及其意义

抵抗素通过减弱胰岛素信号级联反应中多个环节的作用减弱胰岛素的作用,导致胰岛素抵抗(IR),另外,抵抗素可以通过激活核因子-KB(NF-KB)信号途径促进炎症细胞因子肿瘤坏死因子(TNF)α等的产生,参与非酒精性肝病(NAFLD)的发生与发展.     

非酒精性脂肪性肝病患者肝脏固醇调节元件结合蛋白-1c的表达及其意义

目的 研究非酒精性脂肪性肝病(NAFLD)患者肝组织因醇凋节元件结合蛋白-1c(SREBP-1c)的表达变化,探讨其在NAFLD中的作用. 方法对临床与病理确诊的NAFLD患者,检测肝组织SREBP-1c蛋白质和mRNA的表达变化及脂肪酸合成酶的表达,并对相应的临床资料进行分析. 结果 NAFLD患者肝脂肪变程度与血清甘油三酯和胆固醇含量呈明显正相关(r值分别为0.71和0.70,P值均<0.05);NAFLD患者肝SREBP-1c表达在蛋白质和mRNA水平都明显增强,分别为2.19±0.31和0.69±0.02,高于对照组的1.15±0.20和0.40±0.02(t值分别为11.06和-14.63,P值均<0.05),且其表达强度随脂变程度的加重,由1.47±0.08和0.67±0.08增加至2.82±0.78和0.85±0.04(F=24.54,P<0.01),而与是否合并糖尿病无关; NAFLD患者肝脂肪酸合成酶表达增加,脂肪酸合成增加. 结论肝细胞SREBP-1c表达增加,导致脂肪酸合成酶蛋白增加,脂肪合成增加是NAFLD患者肝脂肪蓄积的原因之一.     

PNPLA3基因多态性与非酒精性脂肪性肝病关系的研究进展

非酒精性脂肪性肝病(NAFLD)已成为西方发达国家慢性肝病的首要病因,在我国已成为仅次于慢性病毒性肝炎的第二大肝病.但是其发病机制尚不清楚,目前仍然没有有效的治疗方式,有研究指出NAFLD与遗传、环境、精神心理因素有关,而且接触相似危险因素的个体间NAFLD的发病率差异较大,疾病进程亦不尽相同,这一事实提示遗传因素及基因多态性与NAFLD发病及进程有关.全基因组关联研究发现PNPLA3(patatin - like phospholipase domain containing 3)基因多态性与NAFLD的遗传易感性及进展有着密切的联系.本综述主要从PNPLA3的结构特征、PNPLA3基因的生物学特征及PNPLA3基因多态性与NAFLD的相关性几个方面进行探讨,从而有利于NAFLD发病机制的阐明,对NAFLD的预防和治疗提供可能.     

门冬氨酸-鸟氨酸颗粒剂治疗非酒精性脂肪性肝炎的多剂量平行对照临床研究

目的 研究门冬氨酸-鸟氨酸颗粒剂治疗非酒精性脂肪性肝炎的临床疗效和安全性.方法 用多中心开放性多剂量平行对照的临床试验设计选择非酒精性脂肪性肝炎患者,分别用门冬氨酸-鸟氨酸颗粒剂高剂量(6g,2次/d,口服)和低剂量(3 g,2次/d,口服)治疗12周,观察其疗效和安全性.对不同资料采用pearson x 2检验或Fisher确切概率法、t检验或非参数检验进行统计学分析.结果 本试验共有87例患者入选,高剂量组42例,低剂量组45例;共脱落15例,高剂量组4例,低剂量组11例;实际完成病例数72例,高剂量组38例,低剂量组34例.治疗后两组患者的肝脾CT比值分别为0.89±0.19及0.80±0.15,与治疗前相比,S值分别为329及246;P值均＜ 0.0001,差异均有统计学意义;并且高剂量组疗效优于低剂量组(Z=-2.1042,P＜ 0.05);高剂量组总有效率为52.63％,低剂量组总有效率为38.23％.与治疗前相比,ALT水平均显著降低,高、低剂量组治疗6周S值分别为324.5、223.0,P值均＜0.0001;治疗12周S值分别为370.5、297.5,P值均＜0.0001,差异均有统计学意义;且治疗12周后高剂量组ALT水平的降低较低剂量组更明显.高剂量组降ALT的总有效率为78.95％,高于低剂量组的52.94％.高、低剂量组6周和12周治疗后AST、y-谷氨酰转移酶显著低于治疗前,差异均有统计学意义.治疗12周后,两组的甘油三酯水平也较治疗前降低.共报道4例(4.6％)不良反应,其中低剂量组2例(4.4％),高剂量组2例(4.8％),均为胃肠道反应.结论 门冬氨酸-鸟氨酸颗粒剂治疗非酒精性脂肪性肝炎具有一定的临床疗效,且安全性好.     

非酒精性脂肪性肝病患者尿酸水平与人体测量学指标的研究

目的：探讨非酒精性脂肪性肝病患者人体测量学指标与血尿酸水平的关系。方法选择2010年1月至2012年8月经彩色多普勒超声及肝组织活检诊断为NAFLD患者109例为NAFLD组,选择同期健康体检者47例为非NAFLD组。常规测量两组人员人体测量学指标[身高、体质指数、腰围（WC）、臀围]及生物化学指标[空腹血糖（FBG）、甘油三酯（TG）、总胆固醇（TC）、血尿酸（SUA）]。结果与非NAFLD组相比,NAFLD组患者BMI显著增高（P =0.000）,腰围（WC）亦显著增高（P男性=0.000;P女性=0.026）。NAFLD组男性人员患者腰臀比（WHR）明显高于非NAFLD组男性人员患者（P =0.000）,而两组女性人员患者WHR差异无统计学意义（P =0.119）。相对于非NAFLD组, NAFLD组男性患者血尿酸（SUA）水平明显高于非NAFLD组（P =0.000）,而两组女性人员患者SUA水平差异亦无统计学意义（P =0.386）。结论高尿酸血症（HUA）与NAFLD患者人体测量学指标变化及性别相关。     

小鼠非酒精性脂肪性肝病模型的建立与评价

非酒精性脂肪性肝病（NAFLD）疾病谱包括单纯性脂肪肝、脂肪性肝炎及肝硬化等多种类型。建立一个稳定可靠的、疾病谱完整的NAFLD动物模型，对研究NAFLD的发病机制及治疗方法有重要的意义。本研究采用胆碱和蛋氨酸缺乏的饲料喂养小鼠，旨在建立NAFLD的小鼠模型。[第一段]     

Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis

BACKGROUND & AIMS: The pathogenesis of nonalcoholic steatohepatitis (NASH) remains poorly understood. Although apoptosis is a common mechanism of liver injury, the extent and clinical significance of apoptosis in NASH has not been examined. Thus, the aims of this study were to quantify hepatocyte apoptosis in NASH, correlate it with disease severity, and identify possible mechanisms of apoptosis induction. METHODS: Hepatocyte apoptosis was assessed in NASH, simple steatosis, alcoholic hepatitis, and controls without liver disease using the TUNEL assay and immunohistochemistry for activated caspases 3 and 7. Liver specimens were also graded according to the magnitude of inflammation and fibrosis. RESULTS: TUNEL-positive cells were significantly increased in liver biopsy specimens from patients with NASH compared with simple steatosis and controls. Unexpectedly, TUNEL-positive cells were also greater in NASH vs. alcoholic hepatitis. Immunohistochemistry demonstrated active caspases 3 and 7 in NASH specimens, confirming the occurrence of apoptosis in this disease. A positive correlation was observed between hepatocyte apoptosis and hepatic fibrosis and inflammatory activity, respectively. The Fas receptor was strongly expressed in hepatocytes in liver specimens from NASH patients as compared with controls. CONCLUSIONS: Hepatocyte apoptosis is significantly increased in patients with NASH and correlates with disease severity, suggesting that antiapoptotic therapy may be useful in this syndrome.     

The natural history of nonalcoholic fatty liver disease: a population-based cohort study

BACKGROUND & AIMS: The natural history of nonalcoholic fatty liver disease (NAFLD) in the community remains unknown. We sought to determine survival and liver-related morbidity among community-based NAFLD patients. METHODS: Four hundred twenty patients diagnosed with NAFLD in Olmsted County, Minnesota, between 1980 and 2000 were identified using the resources of the Rochester Epidemiology Project. Medical records were reviewed to confirm diagnosis and determine outcomes up to 2003. Overall survival was compared with the general Minnesota population of the same age and sex. RESULTS: Mean (SD) age at diagnosis was 49 (15) years; 231 (49%) were male. Mean follow-up was 7.6 (4.0) years (range, 0.1-23.5) culminating in 3192 person-years follow-up. Overall, 53 of 420 (12.6%) patients died. Survival was lower than the expected survival for the general population (standardized mortality ratio, 1.34; 95% CI, 1.003-1.76; P = .03). Higher mortality was associated with age (hazard ratio per decade, 2.2; 95% CI, 1.7-2.7), impaired fasting glucose (hazard ratio, 2.6; 95% CI, 1.3-5.2), and cirrhosis (hazard ratio, 3.1, 95% CI, 1.2-7.8). Liver disease was the third leading cause of death (as compared with the thirteenth leading cause of death in the general Minnesota population), occurring in 7 (1.7%) subjects. Twenty-one (5%) patients were diagnosed with cirrhosis, and 13 (3.1%) developed liver-related complications, including 1 requiring transplantation and 2 developing hepatocellular carcinoma. CONCLUSIONS: Mortality among community-diagnosed NAFLD patients is higher than the general population and is associated with older age, impaired fasting glucose, and cirrhosis. Liver-related death is a leading cause of mortality, although the absolute risk is low.     

非酒精性脂肪性肝炎患者肠道菌群的变化及意义

目的探讨非酒精性脂肪性肝炎肠道菌群的变化及意义。方法选择肠道菌群中具有代表性的细菌共5种进行培养和计数。选择健康正常成人、单纯性非酒精性脂肪肝和非酒精性脂肪性肝炎(NASH)患者各30例,计数各组肠道菌群中5种细菌的数量,比较各组细菌数量的变化。结果 NASH组患者存在不同程度的肠道菌群失调,主要表现为厌氧菌减少(P<0.05),而需氧菌显著增多(P<0.05),而兼性厌氧菌酵母样真菌没有显著变化(P>0.05)。结论 NASH患者存在肠道菌群失调、革兰阴性杆菌过度生长的现象,提示肠道微生态失衡可能参与了NASH的发生发展。     

非酒精性脂肪肝患者血浆抵抗素水平测定及与胰岛素抵抗的相关性

目的 探讨血浆抵抗素水平变化在非酒精性脂肪肝（NAFLD）发病中的作用及与胰岛素抵抗（IR）的关系。方法选择32例单纯NAFLD患者（F组）、29例NAFLD并2型糖尿病患者（FD组）和30例体检正常者（对照组）,分别测定空腹血浆抵抗素、空腹血糖（FPG）及胰岛素（FINS）水平,计算胰岛素敏感指数（ISI）,并分析其相关性。结果F组和FD组血浆抵抗素水平、FINS及ISI均明显高于对照组,尤以FD组为著;且血浆抵抗素水平与FINS、FPG呈正相关,与ISI呈负相关。结论NAFLD患者血浆抵抗素水平升高（尤以并2型糖尿病者为著）,并与ISI呈负相关;此可能在NAFLD等IR相关性疾病的发生、发展中具有一定作用。     

吡格列酮对大鼠非酒精性脂肪性肝病的预防作用

非酒精性脂肪性肝病（NAFLD）是临床常见肝病之一，随着生活方式及膳食结构的改变，NAFLD的发病率明显增高。其发病机制目前尚不明确，有研究认为胰岛素抵抗（IR）是导致NAFLD的重要病因之一。吡格列酮作为过氧化物酶体增殖物激活受体γ的高亲和力激动剂，能明显增强组织对胰岛素的敏感性。我们通过高脂饮食建立NAFLD的动物模型，用吡格列酮进行干预，探讨IR与NAFLD的关系，评估吡格列酮对NAFLD的预防作用。     

Hepatocellular carcinoma: epidemiology and molecular carcinogenesis

Primary liver cancer, which consists predominantly of hepatocellular carcinoma (HCC), is the fifth most common cancer worldwide and the third most common cause of cancer mortality. HCC has several interesting epidemiologic features including dynamic temporal trends; marked variations among geographic regions, racial and ethnic groups, and between men and women; and the presence of several well-documented environmental potentially preventable risk factors. Moreover, there is a growing understanding on the molecular mechanisms inducing hepatocarcinogenesis, which almost never occurs in healthy liver, but the cancer risk increases sharply in response to chronic liver injury at the cirrhosis stage. A detailed understanding of epidemiologic factors and molecular mechanisms associated with HCC ultimately could improve our current concepts for screening and treatment of this disease.     

普罗布考对大鼠非酒精性脂肪性肝病的预防及机制研究

目的 观察普罗布考对大鼠非酒精性脂肪性肝病（NAFLD）的预防作用．并探讨其可能作用机理。方法 24只雄性sD大鼠随机分3组：正常对照组、NAFLD对照组、普罗布考干预组。以高脂饲料饲养诱发脂肪肝大鼠模型。18周末，处死所有动物，检测血脂、肝功能、肝脂质含量、氧化还原指标、肝组织病理学等。结果与NAFLD对照组比较，普罗布考干预组TC（2．98±0．90）mmol／L vs（4．45±1．15）mmol／L，ALT（78．25±18．47）U／L vs（110．2±36．33）U／L及肝组织TG含量（2．61±0．20）mmol／L vs（2．93±0．36）mmol／L均显著下降（P均〈0．05），其肝脂肪变性及炎症程度亦显著减轻（P均〈0．05）。结论 普罗布考可对高脂饲料饲养诱发的大鼠NAFLD产生保护作用；其保护作用与提高机体抗氧化能力．减轻组织氧化应激损害有关。     

脂联素及其在非酒精性脂肪性肝病中的作用研究进展

非酒精性脂肪性肝病(NAFLD)已成为危害人类健康的主要消化道疾病之一,及早发现和治疗NAFLD已引起广泛的关注。对于NAFLD的发病机制至今仍存在争议,但与代谢综合征(中心性肥胖、高甘油三酯血症、低高密度脂蛋白胆固醇血症、口服葡萄糖耐量试验异常和高血压等)具有一定的相关性,而脂联素在代谢综合征的发生、发展过程中起着重要的     

大鼠非酒精性脂肪性肝纤维化形成过程中骨桥蛋白的表达及其意义

目的 通过观察非酒精性脂肪性肝纤维化形成过程中肝组织内骨桥蛋白(OPN)的变化规律,探讨OPN在非酒精性脂肪性肝纤维化形成过程中的作用. 方法选用纯系Wistar雄性大鼠56只,体质量180～200g,随机分为正常对照组和高脂饮食4、8、12,16、20、24周组(其中每组各8只).肝组织常规进行HE及Masson三色胶原染色,免疫组织化学染色检测肝组织α-平滑肌肌动蛋白的表达,RT-PeR、Western blot观察肝组织中OPN动态变化.结果 与正常对照组相比,高脂饲料组大鼠肝脏内OPN含量明显升高,随着脂肪肝程度的加重,OPN表达逐渐增强,mRNA及蛋白质表达比较,F值分别为7.30和7.15,尸值均<0.01;与α-平滑肌肌动蛋白表达及肝组织胶原纤维面积百分比呈显著正相关(r值分别为0.94和0.82,P值均<0.01).结论 在非酒精性脂肪性肝纤维化形成过程中,OPN在肝组织中表达显著上调,可能在非酒精性脂肪性肝纤维化的形成过程中发挥重要作用.